EP1222927B1 - Pharmazeutische Zusammensetzungen mit appetitunterdrückender Aktivität - Google Patents

Pharmazeutische Zusammensetzungen mit appetitunterdrückender Aktivität Download PDF

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EP1222927B1
EP1222927B1 EP02004100.0A EP02004100A EP1222927B1 EP 1222927 B1 EP1222927 B1 EP 1222927B1 EP 02004100 A EP02004100 A EP 02004100A EP 1222927 B1 EP1222927 B1 EP 1222927B1
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compound
formula
methyl
treating
produce
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French (fr)
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EP1222927A2 (de
EP1222927A3 (de
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Fanie Retief Van Heerden
Robert Vleggaar
Roelof Marthinus Horak
Robin Alec Learmonth
Vinesh Maharaj
Rory Desmond Whittal
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Council for Scientific and Industrial Research CSIR
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/33—Cactaceae (Cactus family), e.g. pricklypear or Cereus
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A61K31/78—Polymers containing oxygen of acrylic acid or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/27—Asclepiadaceae (Milkweed family), e.g. hoya
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/04—Disaccharides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/08—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to sulfur, selenium or tellurium
    • C07H5/10—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to sulfur, selenium or tellurium to sulfur
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J15/00—Stereochemically pure steroids containing carbon, hydrogen, halogen or oxygen having a partially or totally inverted skeleton, e.g. retrosteroids, L-isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J17/005—Glycosides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
    • C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
    • C07J7/0025—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa substituted in position 16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
    • C07J7/0025—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa substituted in position 16
    • C07J7/0035—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa substituted in position 16 by a hydroxy group free esterified or etherified
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/0065—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by an OH group free esterified or etherified
    • C07J7/007—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by an OH group free esterified or etherified not substituted in position 17 alfa
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

  • This invention relates to carbohydrate intermediates useful in synthesising steroidal glycosides, and to processes for the preparation thereof.
  • Specific embodiments of the first aspect of the invention are thus the compound of formula (37), the compound of formula (38), the compound of formula (39), the compound of formula (40), the compound of formula (48), the compound of formula (49), the compound of formula (50A), the compound of formula (50B), and the compound of formula 50(B) in admixture with a compound of formula (50A).
  • a process for the preparation of a carbohydrate intermediate which is a monosaccharide cymarose moiety which comprises the step of treating the compound of the formula with PhSSiMe 3 , ZnI 2 and Bu4 + I - to produce a compound 4-O-benzoyl-3-O-methyl-6-deoxy- ⁇ -D-phenylthioaltroside of the formula
  • a process for the preparation of a carbohydrate intermediate which is a monosaccharide cymarose moiety which comprises the steps of treating the compound of the formula with PhSSiMe 3 , ZnI 2 and Bu4 + I - to produce a compound 4-O-benzoyl-3-O-methyl-6-deoxy- ⁇ -D-phenylthioaltroside of the formula and treating the compound (37) with diethylaminosulphur trifluoride (DAST) to produce a compound 4-0-benzoyl-3-O-methyl-2-phenylthio-2,6-dideoxy- ⁇ -D-fluorocymaro-pyranoside having the formula:
  • a process for the preparation of a carbohydrate intermediate which is a monosaccharide cymarose moiety which comprises the steps of treating the compound of the formula with PhSSiMe 3 , ZnI 2 and Bu4 + I - to produce a compound 4-O-benzoyl-3-O-methyl-6-deoxy- ⁇ -phenylthioaltroside of the formula treating the compound (37) with t-butyldimethylsilylchloride and imidazole in a solvent to produce 4-O-benzoyl-3-O-methyl-2-O-t-butyldimethyl-silyl- ⁇ -D-phenylthioaltroside having the formula: and treating the compound (39) with a base to produce the monosaccharide 3-O-methyl-2-O-t-butyldimethysilyl- ⁇ -D-phenylthioaltroside having the formula:
  • a process for the preparation of a carbohydrate intermediate which is an activated thevetose moiety which comprises the steps of treating the compound with phenylthiotrimethylsilane and trimethylsilyl-trifluoromethanesulphonate to produce a compound 4-0-benzoyl-3-O-methyl-1-phenylthio-6-deoxy- ⁇ -glucopyranoside having the formula: treating the compound (48) with pivaloyl chloride and a solvent to produce a compound 4-0-benzoyl-3-0-methyl-2-O-pivaloyl-1-phenylthio-6-deoxy- ⁇ -glucopyranoside having the formula: and treating the compound (49) with a brominating agent and diethylaminosulphur trifluoride to produce the monosaccharide compound 4-O-benzoyl-3-O-methyl-2-O-pivaloyl-1-fluoro-6-deoxy-
  • Specific embodiments of the first aspect of the invention are thus the compound of formula (40) producible by the third embodiment of the process of the invention, and the compound of formula (50 A) or formula (50 B) producible by the fourth embodiment of the process of the invention.
  • This compound was found by the applicant in a purified fraction prepared from an extract of a plant of the genus Trichocaulon or of the genus Hoodia and having good appetite suppressant activity.
  • the appetite suppressant active principle in the fraction was identified to be the compound of formula (1) by conventional chemical techniques including nuclear magnetic resonance.
  • the other compounds having the structural formula (2) are analogues and derivatives of the steroidal trisaccharide compound of formula (1), having appetite suppressant properties. These analogues or derivatives are intended to affect the properties of the steroidal trisaccharide with the aim of increasing the activity of the active ingredient. The following effects were taken into consideration when the analogues were chosen:
  • R alkyl
  • R 1 H, alkyl, tigloyl, benzoyl, or any other organic ester group
  • R 2 H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose molecules, or combinations thereof; and in which the broken lines indicate the optional presence of a further bond between C4 - C5 or C5 - C6.
  • R alkyl
  • R 1 H, alkyl, tigloyl, benzoyl, or any other organic ester group
  • R 2 H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose molecules, or combinations thereof; and in which the broken lines indicate the presence of a further bond between C4 - C5 or C5 - C6.
  • R alkyl
  • R 1 H, alkyl, tigloyl, benzoyl, any other organic ester group
  • R 2 H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose molecules, or combinations thereof; and in which the broken lines indicate the optional presence of a further bond between C4 - C5, C5 - C6 or C14 - C15.
  • R alkyl
  • R 1 H, alkyl, tigloyl, benzoyl, any other organic ester group
  • R 2 H, or one or more 6-deoxy carbohydrates, or one or more 2,6-dideoxy carbohydrates, or glucose molecules, or combinations thereof; and in which the broken lines indicate the optional presence of a further bond between C4 - C5, C5 - C6 or C14 - C15
  • R 3 H, alkyl, aryl, acyl, or glucoxy.
  • R H, alkyl, aryl or any steroid possessing a C14 beta hydroxy group, or a C12 beta hydroxy functionality, or a C17 acyl group, or a C5 - C6 olefin, or combinations thereof.
  • the invention relates to intermediates useful in a process for synthetically producing these compounds having appetite suppressant activity.
  • the process uses a steroid as a starting material (or intermediate or precursor), the steroid having the chemical formula
  • the steroid (15) can be prepared from a compound having the formula (22) by a process which includes the steps of
  • a process for the preparation of steroid includes the steps of
  • Reaction Scheme A depicts the procedure for the preparation of steroid intermediate (15) from compound (22) according to "the first alternative procedure” (and includes the preparation of compound (22) from compound (16) for illustrative purposes).
  • a process for the preparation of steroid includes the steps of
  • Reaction Scheme B shows the procedure for the preparation of steroid intermediate (15) from compound (22) according to "the second alternative procedure"
  • Compound (1) may be synthesized from a first carbohydrate intermediate in the form of an activated monosaccharide cymarose moiety, which can be prepared in accordance with the present invention from the compound having the formula (36).
  • Compound (36) can be prepared by a process which includes the steps
  • the invention therefore provides a process for the preparation of a carbohydrate intermediate in the form of an activated monosaccharide cymarose moiety which includes the steps of
  • the invention also extends to a compound of formula (40) producible by this process.
  • Reaction Scheme C shows the procedure for the synthesis of the activated monosaccharide cymarose moiety (40) from compound (36) according to the invention (and includes the preparation of compound (36) from compound (31) for illustrative purposes).
  • compound (1) may also involve a second carbohydrate intermediate in the form of an activated monosaccharide thevetose moiety, which can be prepared in accordance with the present invention from the compound having the formula (47).
  • Compound (47) can be 5 prepared by a process which includes the steps of
  • the invention therefore provides a process for the preparation of an activated monosaccharide thevetose moiety which includes the steps of
  • the invention also extends to a compound of formula (50A) or formula (50B) producible by thus process.
  • Reaction Scheme D shows the procedure for the synthesis of the activated monosaccharide thevetose moiety (50(A) and 50(B)) from compound (48) according to the invention (and includes the preparation of compound (47) from compound (41) for illustrative purposes).
  • a process of synthetically producing a compound of the formula (1) and analogues and derivatives thereof is enabled which includes the steps of synthesising a suitable steroid intermediate or precursor and coupling the required number of suitable monosaccharides with the steroid intermediate.
  • the monosaccharides may include the monosaccharide cymarose moiety or the activated thevetose moiety prepared in accordance with the process of the present invention, or any of the compounds of the present invention.
  • the process of coupling a monosaccharide cymarose with the steroid intermediate may include the steps of
  • the process may include coupling a monosaccharide cymarose moiety to a monosaccharide thevetose moiety and coupling the resultant disaccharide with the combined steroid product (52) to form compound (1).
  • the process of coupling the monosaccharide cymarose moiety to the monosaccharide thevetose moiety and coupling the resultant disaccharide to the combined steroid product (52) may include the steps of
  • Reaction Scheme E shows the procedure for the synthesis of intermediates (52) and (55) and coupling them to form compound (56).
  • An alternative process includes coupling cymarose and thevetose moieties to form a trisaccharide and coupling the trisaccharide onto a steroid derivative to form a compound of the formula (1).
  • the process of forming the trisaccharide and coupling the resultant trisaccharide to a steroid derivative may include the steps of
  • the steroid intermediate (59) may be produced by treating steroid (15) with tiglic acid chloride.
  • Reaction Scheme F shows the procedure for the synthesis of the trisaccharide (58) and the synthesis of compound (1) by coupling the trisaccharide (58) with the steroid intermediate (59).
  • composition or formulation having appetite suppressant activity may comprise an active ingredient which is a synthetically produced compound of the formula (1) or a derivative or analogue thereof, as hereinbefore set out with reference to compounds (2) to (14).
  • the appetite suppressant agent may be a synthetic chemical compound of the formula: or derivatives or analogues thereof, as set out before.
  • the appetite suppressant composition or formulation may consist of the appetite suppressant agent admixed with a pharmaceutical excipient, diluent or carrier.
  • a pharmaceutical excipient diluent or carrier.
  • suitable additives including a stabilizer and such other ingredients as may be desired may be added.
  • the compound (1) or its derivatives or analogues may thus be used in the manufacture of a medicament having appetite suppressant activity.
  • a method of suppressing an appetite may include administering to a human or animal an effective dosage of a composition as described above.
  • a foodstuff or a beverage may contain an effective quantity of the steroidal glycoside of the formula (1), or its derivatives or analogues as set out before, to have an appetite suppressant effect when ingested.
  • neuropeptide "Y” which is negatively regulated by leptin, has been established as one of the positive regulators of feeding behaviour.
  • Expression of the endogenous antagonist for melanocortin receptors has also been shown to be the basis for obesity in a particular model (the ob/ob mouse). Indeed deficiency at the MC4 melanocortin receptor completely replicates the obesity syndrome.
  • Other mediators which have been shown to have roles in the energy balance include bombesin, galonin and glucagon-like peptide-1.
  • compound (1) and its analogues as described above act as an agonist of the melanocortin 4 receptor.
  • the effect of this is to regulate NPY but also to increase cholecystokinin.
  • the effect of cholecystokinin amongst other things is to inhibit gastric emptying.
  • the carbohydrate intermediates of the present invention may be used in the synthesis of compound (1) and analogues and derivatives thereof.
  • the extraction, purification and efficacy of appetite suppressant extracts and the compound of formula (1) is described in the Figures.
  • the appetite suppressant activity of the active extract can be illustrated by way of a typical example of the effect of the methanol extract of Trichocaulon piliferum on rats, by way of the graphic representation in Figure 2 .
  • test group of rats dosed with the extract on day 5 displayed a substantially diminished food intake over the next two days, while a control group did not disclose a comparable reduced food intake.
  • the food intake of the test group returned to normal, and in fact increased, from day 8 onwards.
  • plant material of the genus Trichocaulon or the genus Hoodia is fed into a blender 3, eg a Waring blender, by way of feedline 1, with a solvent in the form of a methylene chloride/methanol solution introduced via feedline 2.
  • the homogenised product is fed via line 4 into a separation stage 5, eg in the form of a filter or centrifuge, and the residual plant material is removed via line 27.
  • the solvent/extract mixture is fed via line 6 into an evaporation stage 7, where the solvent is removed, for example by means of a rotor evaporator.
  • the dried crude extract is fed via line 8 into a further extraction stage 9 with the addition of a methylene chloride/water solution introduced via feedline 29 for further extraction, and then to a separation stage 13 by way of line 11, where the water fraction is removed via line 31.
  • the dissolved extract fraction is fed via line 15 into a drier stage 17 where the solvent is evaporated, for example by a rotor evaporator.
  • the dried extract is fed via line 10 into an extraction stage 12.
  • a methanol/hexane solution is also fed via line 14 into the extraction stage 12 for further purification and extraction of the dried extract.
  • the extract/methanol/hexane mixture is fed via line 16 into a separation stage 18, the hexane fraction is removed via line 20, and the methanol/extract mixture is then fed via line 22 into a drying stage 24.
  • the solvent is removed, eg by evaporation on a rotor evaporator.
  • the dried, partially purified active extract is fed via line 26 and with the addition of methanol via line 28 into a solution stage 30, and the dissolved fraction is fed via line 36 to a chromatography column 38.
  • the methanol soluble fraction is further fractionated, using silica gel and a chloroform/30% methanol solvent, into different fractions schematically indicated as fractions I to V.
  • the fractionation procedure yielded the following fraction weights : I(3.9 g); II(2.6 g); III(2.1 g); IV(1.1 g) and V(2.0 g).
  • fractions are individually evaluated by a suitable bioassaying procedure (in a step not shown) and those fractions identified as fractions I and II, displaying marked appetite suppressant activity, are fed by feedlines 40 and 42 into columns 44 and 46 respectively where they are further fractionated and purified by column chromatography, again by using silica gel and a 9:1 chloroform:methanol system.
  • the sub-fractions II(A) - (C) obtained from column 44 do not, when assayed, display a noteworthy appetite suppressant activity, and may be recycled for further chromatography.
  • the sub-fractions I(A) - (L) obtained from column 46 are also evaluated (by an assaying step not shown), and the sub-fraction I(C) is found to have marked appetite suppressant activity.
  • fraction I(C)(ii) is fed via line 48 into column 50 for a further fractionation and purification, using silica gel and a 9:1 ethyl acetate:hexane eluent.
  • fraction I(C)(ii) is found, after assaying, to possess marked appetite suppressant activity.
  • the purified product is identified by nuclear magnetic resonance spectroscopy (as indicated in Tables 1 and 2 below), to be compound (1).
  • Table 1 1 H (300.13 MHz) n.m.r. data for compound (1) CDCl 3
  • Compound (1) Hydrogen Atom J(HH)/Hz ⁇ H /p.p.m.
  • Examples 4 to 13 illustrate the synthetic procedures whereby the intermediate compounds and steroid (15) may be prepared according to "the first alternative procedure".
  • Cultures of Calonectria decora are prepared by the inoculation of a culture medium comprised of sucrose (900 g), K 2 HPO 4 (30 g), Czapek concentrate (300 ml), corn steep liquor (300 ml) and distilled water (30 l) (150 X 500 ml flasks). After 5 days of shaking at 26°C, progesterone (16) (150 g) in a suspension of Tween 80 (0,1 % soln., 1,5 l) is added to the flasks.
  • the dihydroxy progesterone (17) (75 g, 0.22 mol) is dissolved in dry pyridine (300 ml) and cooled to 0°C.
  • p-Toluene sulfonyl chloride 46 g, 0,24 mol
  • dry pyridine 200 ml
  • H 2 O 500 ml
  • the water layer is extracted with ethyl acetate (1 l), and the organic extract washed with hydrochloric acid (6M, 3 X 1 l), aqueous saturated sodium bicarbonate (500 ml), aqueous saturated sodium chloride (500 ml), and water (500 ml).
  • the organic layer is dried (MgSO 4 ), filtered and evaporated to yield p-toluene sulfonated progesterone (18) (98 g, 92 %) as a viscous dark yellow oil.
  • the diacetoxy compound (20) (60 g, 0,14 mol) is dissolved in benzene (1 l) and ethylene glycol (60 ml) and p-toluene sulfonic acid (1 g) are added.
  • the benzene is previously refluxed with a Dean-Stark trap).
  • the mixture is refluxed with stirring and azeotropic removal of water for 16 hours.
  • Aqueous saturated sodium bicarbonate solution 500 ml is added to the cooled solution. This is then washed with brine (500 ml), and with water (500 ml), and dried (MgSO 4 ).
  • the dienolacetate (21) (35g, 0,077 mol) is suspended in ethanol (500 ml) and sodium borohydride (2,8g, 0.074 mol) is added at 0°C. The mixture is allowed to warm to room temperature and stirred overnight. Most of the solvent is removed in vacuo and the mixture is diluted with water (500 ml) and extracted with ethyl acetate (500 ml). Work-up followed by chromatography on silica gel with acetone/chloroform (1:10) yields the 3ß-alcohol (22) (25 g, 80 %).
  • the 3ß-alcohol (22) (25 g, 60.2 mmol) in dry tetrahydrofuran (300 ml) is added dropwise to a suspension of lithium aluminium hydride (2,7 g, 72,2 mmol) in dry tetrahydrofuran (500 ml).
  • the reaction mixture is stirred at room temperature for 24 hours after which water (2,7 ml) is carefully added and stirred for a further 10 min.
  • Sodium hydroxide (15 % soln, 2,7 ml) is then added and the suspension stirred.
  • N-Bromoacetamide (211 mg, 1,5 mmol) is added to a stirred solution of the 5,14-diene (23) (500 mg, 1,34 mmol) in acetone (100 ml), acetic acid (2,5 ml), and water (5 ml) at 0°C. After 15 min sodium sulphite (5% soln, 50 ml) is added to the reaction mixture. The acetone is evaporated, and the aqueous layer extracted with dichloromethane (3 X 50 ml). The organic layer is dried (MgSO 4 ), filtered and evaporated. Pyridine (1 ml) is added to the product, and stirred for 0,5 h.
  • Dichloromethane (100 ml) is then added to the reaction mixture, and the dichloromethane is washed with citric acid (5 % soln, 3 X 100 ml), saturated sodium bicarbonate (50 ml), and water (50 ml). The organic layer is dried (MgSO 4 ), filtered and evaporated to give the mixture of 14,15- and 5,6-epoxides (360 mg, 69%) as a white foam. The mixture of epoxides could not be separated by silica gel column chromatography.
  • the crude product is purified by silica gel column chromatography using methanol/chloroform (1:9) as solvent to give the unreacted 14,15 epoxy- 20,20-ethylenedioxypregn-5-ene (24) (300 mg, 2,1 %).
  • the 14,15-epoxide (24) (300 mg, 0,77 mmol) in dry tetrahydrofuran (10 ml) is added to a suspension of lithium aluminium hydride (300 mg, 7,89 mmol) in tetrahydrofuran and the reaction refluxed for 48 h. After the addition of water (0,3 ml), sodium hydroxide (15 % soln, 0,3 ml) and filtration as described earlier, the mixture is purified by silica gel column chromatography using methanol: chloroform (1:9) as solvent to give the trihydroxy pregnene (25) (250 mg, 83 %).
  • the ethylenedioxypregnene (25) (250 mg, 0,64 mmol) is dissolved in acetic acid (13,4 ml) and water which after freeze drying affords the trihydroxy steroid (15) (200 mg, 89 %), m.p.: 228°-235°C (lit 225°-235°C), M+ 348, [ ⁇ D ] 20 + 35° (lit [ ⁇ D ] 20 + 29°).
  • Examples 14 to 19 illustrate the synthetic procedures whereby the intermediate compounds and steroid (15) may be prepared according to "the second alternative procedure".
  • the solution was extracted with ethyl acetate (2x50 ml), the ethyl acetate layer was washed citric acid (5x50 ml), saturated sodium bicarbonate solution (100 ml), saturated sodium chloride solution (100 ml) and water (100 ml).
  • 3ß,12ß,14-Trihydroxy-14ß-pregn-5-en-20-one (15a): ⁇ H 0.963 (1H, s, 19-H), 1.192 (3H, s, 18-H), 2.236 (3H, s 21-H), 3.325 (1H, dd, 3 J 11.2 Hz, 3.9 Hz, 12-H), 3.464 (1H, s, OH), 3.5140 (1H, m, 3-H), 3.598 (1H, dd, 3 J 9.6 Hz, 9.6 Hz, 17-H), 4.255 (1H, s, OH), 5.383 (1H, m, 5-H).
  • Examples 20 to 28 illustrate the procedures whereby the intermediate compounds may be prepared to form the first monosaccharide (40).
  • a mixture of methyl- ⁇ -D-glucopyranoside (30 g, 0,15 mol), benzaldehyde (70 ml) and zinc chloride (20 g) is stirred at room temperature for 24 hours.
  • the reaction product is poured into ice water and stirring continued for 15 min.
  • the white precipitate is filtered and washed with diethyl ether.
  • the solid material is stirred with a solution of sodium metabisulphite (10 % soln), for 15 min, filtered and washed with water.
  • the solid material is crystallized from chloroform and ether to yield the benzylidene product (32) (31 g, 72 %).
  • p-Toluene sulfonyl chloride 25 g, 1,2 eq
  • pyridine 100 ml
  • benzylidene glucose 31 g, 0.12 mol
  • pyridine 100 ml
  • the reaction is stirred at room temperature for 48 hours. Ice is added to the reaction mixture.
  • the resulting white solid material is washed with water and recrystallized from hot ethanol to yield the tosylated glucose (33) (28 g, 60 %).
  • the tosylate (33) (28 g, 64 mmol) in a solution of sodium (7 g) in methanol (150 ml) is heated at 110°C for 48 hour in an autoclave.
  • the reaction vessel is cooled and solid carbon dioxide is added to the reaction mixture.
  • the methanol is evaporated and the solid material is then taken up in water.
  • the aqueous layer is extracted with chloroform (X 3).
  • the chloroform is dried (MgSO 4 ), filtered and evaporated.
  • the crude mixture is purified by silica gel column chromatography eluting with chloroform : acetone (9:1) to yield the altroside (34) (10 g, 52 %).
  • the benzylidene altroside (34) (10 g, 33 mmol) is added to a solution of N-bromosuccinimide (7.6 g) and barium carbonate (20 g) in carbon tetrachloride and the reaction mixture is refluxed at 75°C for 3 hours. The reaction mixture is filtered and the carbon tetrachloride layer is washed with water. The organic layer is dried (MgSO 4 ), filtered and evaporated to yield 6-bromo-altroside (35), (9 g, 69 %).
  • Phenylthiotrimethylsilane (5 ml) and trimethylsilyltrifluoromethane sulphonate (2 ml) are added at 0°C to a solution of the 6-deoxy-altroside (36) (5 g, 17 mmol) in dichloromethane (200 ml).
  • the reaction mixture is stirred at room temperature for 6 hours.
  • Saturated sodium bicarbonate is added to the reaction mixture.
  • the dichloromethane layer is dried (MgSO 4 ), filtered and evaporated.
  • the crude mixture is purified by silica gel column chromatography eluting with chloroform : acetone (9:1) to yield the ⁇ ß-phenylthioaltroside (37) (4 g, 63 %).
  • Diethylaminosulphurtrifluoride (0,65 g) is added rapidly to a solution of the ⁇ ß-phenylthioaltroside (37) (0,5 g, 1,33 mmol) in dichloromethane at 0°C.
  • the reaction is stirred for 0,5 h at 0°C and then saturated sodium bicarbonate is added.
  • the dichloromethane is separated from the aqueous layer, dried (MgSO 4 ), filtered and evaporated to yield the ⁇ ß-fluorocymarose (38) (450 mg, 90 %).
  • the 6-deoxy altroside (37) (5 g) is silylated using t-butyldimethylsilylchloride (3 g) and imidazole (3 g) in pyridine (50 ml). The reaction is worked-up by extracting with ethyl acetate, washing the ethyl acetate with hydrochloric acid (6 N), then with sodium bicarbonate, and finally with water. The ethyl acetate layer is dried (MgSO 4 ), filtered and evaporated to yield the silylated benzoyl phenylthioaltroside (39) (80 %).
  • silylated benzoyl phenylthioaltroside (39) (6 g) is treated with sodium methoxide (100 ml) for 4 hours. The methanol is evaporated and water is added to the reaction. The water layer is acidified (pH 5, ACOH) and extracted with ethyl acetate. The ethyl acetate is washed with water, dried (MgSO 4 ), filtered and evaporated to yield silylated methyl phenylthioaltroside (40) (75%).
  • Examples 29 to 37 illustrate the procedures synthetic whereby the intermediate compounds may be prepared to form the second monosaccharide (50).
  • the methyl diisopropylidene compound (43) (38 g, 0,14 mol) is dissolved in acetic acid (50 %, 700 ml) and the solution refluxed for 18 h. After cooling the acetic acid is evaporated.
  • the crude product is purified by column chromatography eluting with chloroform : methanol : acetone : water (70 : 27 : 2 : 1) to yield 3-0-methyl- ⁇ ß-glucopyranoside (44) (13 g, 50 %).
  • the 3-0-methyl- ⁇ -glucopyranoside (44) (10 g) is dissolved in methanol (50 ml) and KCl (conc.) (1 ml) and refluxed overnight. Solid NaHCO 3 is added and the reaction is filtered. The methanol is evaporated to give 1,3-di-0-methyl- ⁇ -D-glucopyranoside (45), (95%).
  • the glucopyranoside (45) (8 g) is stirred at room temperature in a solution of benzalaldehyde (20 ml) and zinc chloride (5 g). After 24 hours, ice is added and the aqueous layer is extracted with chloroform. The chloroform layer is dried (MgSO 4 ), filtered and evaporated. The benzalaldehyde is removed by vacuum distillation and the product is purified by silica gel column chromatography eluting with acetone:chloroform (0,5:9,5), to yield benzylidene- ⁇ -glucopyranoside (46) (60%).
  • the benzylidene compound (46) (5 g) is refluxed at 80°C in a mixture of N-bromosuccinimide (3,7 g) and barium carbonate (4 g) in carbon tetrachloride. After 4 hours, the reaction is filtered and the carbon tetrachloride is washed with water, dried (MgSO 4 ), filtered and evaporated to give the bromo compound (70%).
  • the bromo compound (4,3 g) is dissolved in a solution of ethanol (300 ml) and nickel chloride (8,6 g) at 0°C. To this solution, sodium borohydride (8,6 g) in water (50 ml) is added dropwise over a period of 15 minutes. The reaction mixture is refluxed at 100°C for 45 minutes, cooled, filtered and evaporated. Chloroform is added, and the chloroform layer is washed with water, dried (MgSO 4 ), filtered and evaporated to give the 6-deoxy sugar (47) (70%).
  • the 6-deoxy glucopyranoside (47) (3 g) is dissolved in dichloromethane (50 ml). To this solution, phenylthiotrimethylsilane (2 g) and trimethylsilyltrifluoromethanesulphonate (0,2 ml) are added. The solution is stirred at room temperature overnight, after which saturated sodium bicarbonate is added. The dichloromethane layer is dried (MgSO 4 ), filtered and evaporated. The product is purified by silica gel column chromatography eluting with ethyl acetate:hexane (2:8), to give the compound (48) (60%).
  • pivaloyl chloride (2 ml) is added. The solution is stirred at room temperature overnight after which water is added. The aqueous layer is extracted with ethyl acetate, and the organic layer is washed with HCl (6 N). The organic layer is dried (MgSO 4 ), filtered and evaporated to give the pivaloyl ester (49) (80%).
  • N-Bromosuccinimide (1,2 g) and diethylaminosulphur trifluoride (1,2 g) are added to a solution of the pivaloyl ester (49) (2 g) in dichloromethane (100 ml) at 0°C. After 1 hour, saturated sodium bicarbonate is added. The dichloromethane layer is dried (MgSO 4 ), filtered and evaporated. The ⁇ -fluoropyranoside (50) is purified by silica gel column chromatography eluting with ethyl acetate:hexane (2:8), (yield 45%).
  • Example 38 illustrates the synthetic procedure whereby the compound 3-0- [4-0-benzoyl-2-phenylthio-ß-D-cymaropyranosyl]-12,14ß-dihydroxy-pregnan-5-ene-20-one(51) may be prepared.
  • Tin chloride (190 mg, 1 mmol) is added to a solution of 3,12,14 ß-trihydroxy pregnan-5-ene-20-one (15) (100 mg, 0,28 mmol) and the fluorocymaropyranoside (38) (210 mg, 0,56 mmol), in dry diethyl ether and 4 ⁇ molecular sieves at -15°C.
  • the reaction mixture is maintained at -15°C for 3 days.
  • Saturated sodium bicarbonate is added to the reaction mixture.
  • the ether layer is dried (MgSO 4 ), filtered and evaporated.
  • the product is purified by silica gel column chromatography eluting with chloroform : methanol (9, 5:0,5) to yield the glycoside (51) (30 mg, 15 %).
  • Examples 39 to 41 illustrate the synthetic procedures whereby the cymarose and thevetose moieties may be coupled.
  • a solution of thevetose (50 A) (1,5 g), cymarose (40) (1,3 g), and molecular sieves 4 ⁇ in dichloromethane is stirred at room temperature for 1 hour.
  • the reaction mixture is cooled to -15°C, and tin (II) chloride (0,8 g) and silver trifluoromethanesulphonate (1,1 g) are added.
  • the mixture is stirred at -15°C for 16 hours, after which triethylamine (0,5 ml) is added.
  • the reaction product is filtered and the dichloromethane is evaporated.
  • the dissaccharide (53) is purified by silica gel column chromatography eluting with ethyl acetate:hexane (2:8), yield 15%.
  • dissaccharide (53) 200 mg
  • tetrabutylammonium fluoride 0,4 ml
  • the mixture is stirred at room temperature for 1 hour, after which saturated sodium bicarbonate is added.
  • the reaction mixture is extracted with ethyl acetate and the ethyl acetate layer is dried (MgSO 4 ), filtered and evaporated.
  • the dissaccharide (54) is purified by silica gel column chromatography (acetone:chloroform, 0,5:9,5) yield 60%.
  • a method of treating, preventing or combating obesity in a human or non-human animal may comprise administering to said human or non-human animal an obesity treating, preventing or combating amount of a compound of formula (1).
  • animal as used herein extends to, but is not restricted to, companion animals, e.g. household pets and domesticated animals; non-limiting examples of such animals include cattle, sheep, ferrets, swine, camels, horses, poultry, fish, rabbits, goats, dogs and cats.
  • a compound of formula (1), or a composition comprising the same is advantageously administered to said human in a dosage amount of from about 0.01 mg/kg/day to about 10 mg/kg/day.
  • a preferred dosage range is 0.05 mg/kg/day to 0.5 mg/kg/day.
  • a preferred dosage range is 0.1 mg/kg/day to 20 mg/kg/day; especially preferred is 0.5 mg/kg/day to 5 mg/kg/day.

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Claims (13)

  1. Verfahren zur Herstellung eines Kohlenhydratzwischenprodukts, welches umfasst:
    A. wenn das Kohlenhydratzwischenprodukt ein Monosaccharid-Cymarose-Rest ist, den Schritt des Behandelns der Verbindung der Formel
    Figure imgb0111
     mit PhSSiMe3, ZnI2 und Bu4+I-, um eine Verbindung 4-O-Benzoyl-3-O-methyl-6-deoxy-αβ-D-phenylthioaltrosid der Formel
    Figure imgb0112
     herzustellen; oder
    B. wenn das Kohlenhydratzwischenprodukt ein Monosaccharid-Cymarose-Rest ist, die Schritte des Behandelns der Verbindung der Formel
    Figure imgb0113
     mit PhSSiMe3, ZnI2 und Bu4+I-, um eine Verbindung 4-O-Benzoyl-3-O-methyl-6-deoxy-αβ-D-phenylthioaltrosid der Formel
    Figure imgb0114
     herzustellen und Behandeln der Verbindung (37) mit Diethylaminoschwefeltrifluorid (DAST), um eine Verbindung 4-O-Benzoyl-3-O-methyl-2-phenylthio-2,6-dideoxy-αβ-D-fluorcymaropyranosid mit der Formel
    Figure imgb0115
     herzustellen;
    oder
    C. wenn das Kohlenhydratzwischenprodukt ein Monosaccharid-Cymarose-Rest ist, die Schritte des Behandelns der Verbindung der Formel
    Figure imgb0116
     mit PhSSiMe3, ZnI2 und Bu4+I-, um eine Verbindung 4-O-Benzoyl-3-O-methyl-6-deoxy-αβ-D-phenylthioaltrosid der Formel
    Figure imgb0117
     herzustellen, Behandeln der Verbindung (37) mit t-Butyldimethylsilylchlorid und Imidazol in Pyridin als einem Lösungsmittel, um 4-O-Benzoyl-3-O-methyl-2-O-t-butyldimethylsilyl-αβ-D-phenylthioaltrosid mit der Formel
    Figure imgb0118
     herzustellen, in welcher Ph = Phenyl, Me = Methyl und Z = TBDMS = t-Butyldimethylsilyl, und Behandeln der Verbindung (39) mit einer Base, um das Monosaccharid 3-O-Methyl-2-O-t-butyldimethylsilyl-αβ-D-phenylthioaltrosid mit der Formel:
    Figure imgb0119
     herzustellen, in welcher Ph = Phenyl, Me = Methyl und Z = TBDMS = t-Butyldimethylsilyl; oder
    D. wenn das Kohlenhydratzwischenprodukt ein aktivierter Thevetoserest ist, die Schritte des Behandelns der Verbindung
    Figure imgb0120
     mit Phenylthiotrimethylsilan und Trimethylsilyltrifluormethansulfonat, um eine Verbindung 4-O-Benzoyl-3-O-methyl-1-phenylthio-6-deoxy-αβ-glucopyranosid mit der Formel:
    Figure imgb0121
     herzustellen, Behandeln der Verbindung (48) mit Pivaloylchlorid und Pyridin als einem Lösungsmittel, um eine Verbindung 4-O-Benzoyl-3-O-methyl-2-O-pivaloyl-1-phenylthio-6-deoxy-αβ-glucopyranosid mit der Formel:
    Figure imgb0122
     herzustellen, in welcher Ph = Phenyl, Me = Methyl und Pv = Pivaloyl,
    und Behandeln der Verbindung (49) mit einem bromierenden Mittel und Diethylaminoschwefeltrifluorid, um die Monosaccharidverbindung 4-O-Benzoyl-3-O-methyl-2-O-pivaloyl-1-fluor-6-deoxy-β-glucopyranosid herzustellen, welches als Stereoisomere mit den Formeln:
    Figure imgb0123
     auftritt.
  2. Verbindung ausgewählt aus
    Figure imgb0124
    Figure imgb0125
    Figure imgb0126
    Figure imgb0127
    Figure imgb0128
    Figure imgb0129
    Figure imgb0130
    Figure imgb0131
     worin Ph = Phenyl, Me = Methyl, Pv = Pivaloyl und Z = TBDMS = t-Butyldimethylsilyl.
  3. Eine Verbindung gemäß Anspruch 2, welche eine Verbindung der Formel (40) ist, darstellbar durch ein Verfahren wie in Anspruch 1C beansprucht.
  4. Eine Verbindung gemäß Anspruch 2, welche eine Verbindung der Formel (50A) oder der Formel (50B) ist, darstellbar durch ein Verfahren wie in Anspruch 1 D beansprucht.
  5. Eine Verbindung gemäß Anspruch 2, welche eine Verbindung der Formel (37) ist.
  6. Eine Verbindung gemäß Anspruch 2, welche eine Verbindung der Formel (38) ist.
  7. Eine Verbindung gemäß Anspruch 2, welche eine Verbindung der Formel (39) ist.
  8. Eine Verbindung gemäß Anspruch 2, welche eine Verbindung der Formel (40) ist.
  9. Eine Verbindung gemäß Anspruch 2, welche eine Verbindung der Formel (48) ist.
  10. Eine Verbindung gemäß Anspruch 2, welche eine Verbindung der Formel (49) ist.
  11. Eine Verbindung gemäß Anspruch 2, welche eine Verbindung der Formel (50A) ist.
  12. Eine Verbindung gemäß Anspruch 2, welche eine Verbindung der Formel (50B) ist.
  13. Eine Verbindung gemäß Anspruch 12, in Beimischung mit einer Verbindung der Formel (50A).
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KR100891756B1 (ko) 2009-04-07
GB2360519A (en) 2001-09-26
UA72439C2 (en) 2005-03-15
GB2338235A (en) 1999-12-15
PL201487B1 (pl) 2009-04-30
ES2321162T3 (es) 2009-06-03
ATE344046T1 (de) 2006-11-15
AP2003002729A0 (en) 2003-06-30
DE69836321T2 (de) 2007-06-28
DK0973534T3 (da) 2007-03-12
EA200200392A1 (ru) 2002-08-29
BG103795A (en) 2000-05-31
PL336498A1 (en) 2000-07-03
TW200300093A (en) 2003-05-16
ES2276460T3 (es) 2007-06-16
CA2283564C (en) 2007-07-10
EP1213020A3 (de) 2005-03-09
WO1998046243A3 (en) 1999-02-25
EA002885B1 (ru) 2002-10-31
NZ516695A (en) 2003-08-29

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